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Oculomotor Schwannomas: A Systematic Review and Report of Two Pediatric Cases Treated with Fractionated Cyberknife Stereotactic Radiotherapy
Literature Review
Oculomotor Schwannomas: A Systematic Review and Report of Two Pediatric Cases Treated with Fractionated Cyberknife Stereotactic Radiotherapy Hassan A. Fadel1, Tarek Y. El Ahmadieh2, Aaron R. Plitt2, Om J. Neeley2, Zachary Johnson2, Salah G. Aoun2, Osama Mohamad3, Robert Timmerman2,3, Bradley E. Weprin2,3
Key words Cyberknife - Fractionated radiotherapy - Oculomotor - Pediatric - Schwannoma -
Abbreviations and Acronyms CN: Cranial nerve MRI: Magnetic resonance imaging SRS: Stereotactic radiosurgery SRT: Stereotactic radiotherapy From the 1Wayne State University School of Medicine, Detroit, Michigan; and Departments of 2Neurological Surgery, and 3Radiation Oncology, University of Texas Southwestern, Dallas, Texas, USA To whom correspondence should be addressed: Tarek Y. El Ahmadieh, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.05.114 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Schwannomas are benign peripheral nerve sheath tumors that represent approximately 9% of all primary central nervous system tumors. They originate from the vestibular nerve in 95.5% of cases.1 Nonvestibular intracranial schwannomas commonly arise from the cranial nerves (CNs) traversing the jugular foramen (CN IX, X, and XI), the facial nerve (CN VII), the trigeminal nerve (CN V), or the hypoglossal nerve (CN XII).2-9 Schwannomas of the oculomotor nerve (CN III) are extremely rare, particularly in the pediatric population.10-23 Depending on their location and pattern of growth, oculomotor schwannomas are classified as cisternal, cisternocavernous, or cavernous, with presenting symptoms varying from incomplete oculomotor palsy to clinical sequalae of brainstem compression.24,25 Because of the variability in tumor location, tumor size, and presenting features, the treatment of
- OBJECTIVE:
Pediatric oculomotor nerve schwannomas are rare and challenging lesions due to the high morbidity associated with surgical intervention and their proximity to critical structures limiting the opportunity for stereotactic radiosurgery. We aim to report and review the novel use of fractionated Cyberknife (Accuray, Inc., Sunnyvale, California, USA) stereotactic radiotherapy in pediatric patients with oculomotor schwannomas.
- METHODS:
A systematic review of PubMed, Embase, and Cochrane was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two patients, ages 8 and 10 years, with tumor volumes of 0.1 cm3 and 0.2 cm3, respectively, were treated with fractionated Cyberknife radiotherapy at our institution. A total dose of 45e50 Gy was administered over 25 fractions (1.8e2.0 Gy per fraction) to the 82%L84% isodose line. Serial magnetic resonance imaging was obtained for long-term follow-up (56e58 months).
- RESULTS:
We found 14 articles published between 1982 and 2018 that reported a total of 18 pediatric patients with intracranial oculomotor schwannomas. No previously described cases of pediatric intracranial oculomotor schwannomas were treated with radiation therapy. In both of our patients, radiographic tumor control was achieved at a mean follow-up of 57 months, with 1 patient displaying a decrease in tumor volume. Neither patient exhibited any worsening of their presenting symptoms, nor did either patient develop any new neurocognitive deficits following treatment.
- CONCLUSIONS:
Fractionated Cyberknife radiotherapy is an effective and well-tolerated treatment option for intracranial oculomotor nerve schwannomas with excellent tumor control rates, similar to surgical and radiosurgical techniques, while sparing critical surrounding structures.
pediatric or adult oculomotor schwannomas often is multimodal and includes medical therapy, microsurgical resection, and/or primary or adjunct irradiation. Historically, the standard treatment for nonvestibular schwannomas, including oculomotor schwannomas, has been microsurgical resection. However, this treatment modality has been associated with a relatively high tumor recurrence rate requiring retreatment, as well as a high rate of postsurgical complications and neurologic morbidity.11,13,14,17,20,21,26 Despite recent advances in microsurgical techniques and the development of novel skull base approaches, surgical resection
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of oculomotor schwannomas remains a challenging treatment option that carries invariable risk of diplopia. Stereotactic radiotherapy (SRT) is typically used for unresectable lesions as well as recurrent and residual disease.27-34 Although stereotactic radiosurgery (SRS) has been shown to be effective in targeting other nonvestibular schwannomas, there is limited utility of SRS for lesions of the oculomotor nerve due to the proximity of the optic apparatus that exhibits a high sensitivity to single-fraction radiation (8e10 Gy).35 Conversely, fractionated SRT can be used to target such lesions, as the surrounding optic apparatus has been
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Figure 1. Flow diagram according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement describing the identification,
shown to have a fractionated dose tolerance of 55e60 Gy.36 Therefore, the novel treatment paradigm of fractionated Cyberknife (Accuray, Inc., Sunnyvale, California, USA) SRT combines the dose conformality of SRS with the benefits of fractionation to deliver a highly conformal dose to the target lesion that spares critical surrounding structures. In the following report, we present the clinical course and outcome of 2 pediatric patients with oculomotor schwannomas treated with fractionated Cyberknife (Accuray, Inc.) SRT. These are the first reported cases of oculomotor nerve schwannomas treated with fractionated Cyberknife SRT in the pediatric population. We complement our report with a systematic review of the literature for these extremely rare tumors.
screening, exclusion and inclusion of studies reporting oculomotor schwannomas in pediatric patients.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to collect all cases of pediatric oculomotor schwannomas treated medically, surgically, and/or with primary or adjuvant SRT or SRS.37 A combination of the following key search terms was used to identify all relevant studies: “pediatric,” “oculomotor,” “schwannoma,” “neurilemmoma,” “radiotherapy,” and “radiosurgery.” The primary search was supplemented with a hand-review of the reference sections of all relevant manuscripts. The search was restricted to peer-reviewed studies published in the English language (Figure 1). Assessment of risk of bias across studies was not conducted, given all included articles were observational studies or case reports, for which there is no validated tool for risk of bias assessment.
METHODS Literature Review A systematic review of PubMed, Embase, and Cochrane was completed according to
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CASE DESCRIPTIONS Two recent pediatric patients have been diagnosed with oculomotor schwannomas
and treated with fractionated Cyberknife (Accuray, Inc.) SRT at our institution. Case 1 Our first patient was a 10-year-old female patient at the time of her initial presentation. She had a history of obesity and dyslipidemia and presented with headaches and a right-sided partial third nerve (CN III) palsy. Her CN III palsy evolved over 18 months, with diplopia developing 4 months before presentation. Her headaches were chronic in nature. Magnetic resonance imaging (MRI) of the brain was completed and revealed an 11 5 8 mm (anteroposterior transverse craniocaudal) enhancing mass intimately associated with the cisternal segment of the right-sided third CN with extension into the right cavernous sinus (Figure 2). Formal ophthalmologic evaluation revealed full visual fields with right-sided ptosis and inferior and medial recti weakness. Following discussion in multidisciplinary tumor conference, treatment
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Figure 2. Axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging obtained in a 10-year-old female patient demonstrating an 11-mm anteroposterior 5-mm transverse 8-mm
with fractionated Cyberknife (Accuray, Inc.) SRT was recommended. Between July and August 2012, a total of 45 Gy was administered over 25 fractions (1.8 Gy per fraction) to a gross total volume of 0.46 cm3. The dose was delivered to the 82% isodose line with 96.5% target coverage. Importantly, the maximum optic pathway dose was 34.8 Gy. Follow up MRIs were obtained at 6, 12, 18, 30, 42, and 58 months. The mass exhibited a slight
craniocaudal contrast-enhancing mass involving the cisternal segment of the right oculomotor nerve with protrusion into the right cavernous sinus.
decrease in size at 30 months with stable imaging thereafter (Figure 3). Formal post-treatment ophthalmologic testing was completed every 6 months for the first 18 months followed by annual examinations thereafter. Throughout follow-up, the patient did not develop a new visual field deficit, diminution in visual acuity, or worsening of her pretreatment diplopia. She eventually underwent strabismus correction surgery 15 months after
Figure 3. Five-year follow-up axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging demonstrating stable fusiform enhancing mass
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completion of radiation therapy with subsequent resolution of her diplopia. She is currently being monitored with biannual MRI examinations and continues to follow up with oncology and ophthalmology. Case 2 Our second patient was an 8-year-old male patient at the time of his initial presentation. He presented with alternating exotropia and a right-sided CN III palsy
involving the cisternal segment of the right oculomotor nerve.
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Figure 4. Axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging obtained in an 8-year-old male patient demonstrating a 5.5-mm AP 5-mm transverse 4-mm contrast-enhancing
(ptosis) over a 2-week timeframe. An MRI of the brain revealed a 5.5 5 4 mm (anteroposterior transverse craniocaudal) enhancing lesion intimately involved with the right third CN within the cavernous sinus (Figure 4). Multidisciplinary consensus was again to treat with fractionated Cyberknife (Accuray, Inc.) SRT. Between August and September 2013, a total of 50 Gy was administered over 25 fractions (2 Gy per fraction) to a gross total volume of 0.299 cm3 (Figure 5). The dose was delivered to the 84% isodose line with 99.8% target coverage. The maximum optic pathway dose was 16.5 Gy. Due to persistent post-treatment
diplopia, the patient subsequently underwent right-sided strabismus correction surgery and ptosis repair 12 months after completion of radiation therapy. His diplopia improved over the ensuing 12 months, with continued stable ophthalmologic examinations performed at 6month intervals. His CN III palsy has remained unchanged throughout the post-treatment period. Follow-up MRIs were obtained at 6, 12, 24, 36, and 56 months, with the mass exhibiting no change in size on serial imaging (Figure 6). He is currently being monitored with biannual MRI and continues to follow up with oncology and ophthalmology.
Figure 5. CyberKnife treatment plan for a right oculomotor nerve schwannoma showing the target and nearby organs at risk (brain stem in pink, pituitary in yellow, right and left optic nerves in teal and
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mass in the right cavernous sinus along the course of the right oculomotor nerve. Arrows denote contrast enhancing oculomotor schwannoma.
RESULTS In our systematic review of the literature, we found 14 articles published between 1982 and 2018 reporting a total of 18 pediatric patients with intracranial oculomotor schwannomas (Table 1).10-23 Due to the extreme rarity of oculomotor schwannomas, particularly in the pediatric population, all but 2 published studies are isolated case reports, with 1 case series of 5 patients. Presenting symptoms for pediatric patients with oculomotor schwannomas included ophthalmoplegia (94%), ptosis (61%), headache (50%), and diplopia (33%) (Table 1). Including our patients, the age at presentation ranged between 2 months and
green, and carotid arteries in red). The patient received 50 Gy in 25 fractions. Representative isodose lines are also shown in the axial (A), sagittal (B), and coronal (C) views.
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Figure 6. Five-year follow-up axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging
16 years (mean age of 8 years), with a 12:8 female predominance. Maximal tumor diameters were documented between 1.7 mm and 55 mm (mean diameter of 17.2 mm). The majority of reported pediatric oculomotor schwannomas (10 patients) were treated with total or partial microsurgical resection, whereas 2 patients were treated medically. The method of treatment for 6 patients was not described. Of the 18 previously reported cases of pediatric oculomotor schwannomas, none were treated with radiotherapy. DISCUSSION Microsurgical resection has historically stood as the standard primary treatment modality for pediatric intracranial oculomotor schwannomas.10-14,16,17,20-22 However, microsurgical resection has been associated with a high morbidity rate and the added rare risk of postsurgical complications such as infection, cerebrospinal fluid leak, hydrocephalus, and vasospasm leading to hemiparesis.4,11,13,14,16,17,21,28,32,38 Namely, the improvement and preservation of the oculomotor nerve function has proven to be challenging. Postoperative oculomotor nerve functional improvement has been reported in 11% of patients, with 50% of patients experiencing postoperative functional decline as well as aberrant nerve regeneration.4,14,26,39,40 Furthermore, tumor recurrence of nonvestibular schwannomas
demonstrating stable enhancing lesion within the right cavernous sinus.
following microsurgical resection has been reported to be as high as 17% at 12- to 60month follow-up (25 month mean), with numerous cases of recurrent oculomotor schwannomas requiring retreatment noted in the literature.3,26,28,29,31,32 To date, 10 pediatric patients with oculomotor schwannomas have been treated with microsurgical resection.10-14,16,17,20-22 Of these 10 patients, only 2 experienced postoperative improvement in oculomotor nerve function, one of which was following a subtotal resection complicated by tumor recurrence necessitating re-operation.12,22 Despite the use of careful dissection and graft reconstruction following microsurgery, 6 surgically treated pediatric patients experienced worsening of oculomotor nerve function on long-term follow-up (2e240 months).11,13,14,16,17,21 Fractionated radiotherapy for nonvestibular schwannomas has been shown to achieve excellent tumor control with marginal adverse side effects in adults. Table 2 summarizes all adult cases of oculomotor schwannomas treated with SRT or SRS reported in the literature to date.27-33,41-45 The favorable use of SRS in the treatment of 23 patients with nonvestibular schwannomas (trigeminal [n ¼ 10], jugular foramen [n ¼ 10], hypoglossal [n ¼ 2], and trochlear [n ¼ 1] schwannomas), but not oculomotor schwannomas, was reported by Pollock et al.41 Using a median dose of 18 Gy (12e20 Gy) to target 23 tumors ranging between 0.2 and 17.6 cm3 (8.9
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cm3 mean) in size, local tumor control was achieved in 96% of patients on longterm follow-up (12e111 months), with new neurologic deficits occurring in 3 patients. More recent series using SRS as the primary or adjuvant treatment of nonvestibular schwannomas, including oculomotor schwannomas, have replicated and improved on those results described by Pollock et al., while using lower doses of radiation (Table 2).6,25,28-30,44,46,47 Fractionated radiotherapy (i.e., 25e30 fractions) has proven to be an effective treatment for both vestibular and nonvestibular intracranial schwannomas.32,45,48-50 Targeting vestibular schwannomas with a dose of 45e50 Gy delivered over 25 fractions has been shown to achieve high tumor control rates (>95%) on long-term follow-up as well as progression-free survival rates on par with those of microsurgical resection, while also exhibiting minimal toxic effects.48-54 Zabel et al.45 was the first to report the results of linear accelerator fractionated radiotherapy in 13 adult patients with nonvestibular intracranial schwannomas, including 3 patients with oculomotor schwannomas. The study found that a median dose of 57.6 Gy with 1.8 Gy per fraction targeting a median tumor volume of 19.8 cm3 led to a 100% tumor control rate without any patient developing CN or brainstem deficits on long-term follow-up (median 33 months).
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Age, years, Sex
Presenting Signs and Symptoms
Previous Treatment
Tumor Location
Side (L/R)
Tumor Size, mm
Kansu et al., 198210
15, M
Ophthalmoplegia, ptosis, mydriasis
None
Cis
R
4
Leunda et al., 198211
11, M
Headaches, hemiparesis, ophthalmoplegia
None
ND
L
Niazi and Boggan, 199412
13, M
Headaches, hemiparesis, diplopia, ptosis, anisocoria
None
Cis-cav
Bejjani et al., 199713
6, F
Ophthalmoplegia, diplopia
None
Mariniello et al., 199914
8, F
Ophthalmoplegia, ptosis, exotropia
2 months, M
Ophthalmoplegia, ptosis, anisocoria
2 months, M
Ophthalmoplegia, Anisocoria
None
Cis
L
8 months, F
Anisocoria
None
Cav
R
Study
Norman et al., 200115
Posttreatment CN III Status
Re-Treatment
Gross total resection
ND
ND
ND
55
Gross total resection
108
Worsened CN III palsy
No
R
50
Subtotal resection
111
Improved CN III palsy Resection of recurrent tumor
Cis
R
12
Subtotal resection
4
Worsened CN III palsy
No
None
Cav
L
10
Gross total resection
24
Worsened CN III palsy
No
None
Cav
R
3
ND
7
ND
ND
ND
Ophthalmoplegia, ptosis
None
Cis
L
ND
ND
3, F
Ophthalmoplegia, exotropia
None
Cav
R
ND
ND
Netuka et al., 2003
12, F
Headaches
None
Cis-Cav
L
28
Gross total resection
12
Worsened CN III palsy
No
Murakami et al., 200517
11, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis
L
5
Gross total resection
2
Worsened CN III palsy
No
Bisdorff and Wildanger, 200618
14, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis
R
7
Medical management
Chewning et al., 200819
3, F
Headaches, ophthalmoplegia, anisocoria
None
Cis
R
4
ND
Goel and Shah, 201020
16, M
Headaches, ophthalmoplegia, ptosis
None
Cav
L
53
Gross total resection
24
Unchanged CN III palsy
No
Yang et al., 201321
3, M
Ophthalmoplegia, ptosis
None
Cis
R
11 12 13
Gross total resection
12
Worsened CN III palsy
No
Mariniello et al., 201722
16, F
Ophthalmoplegia, exotropia
None
Cis-Cav
L
1.7 1.5 1.2
Gross total resection
240
Improved CN III palsy
No
Lee et al., 201823
10, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis
R
6
Medical management
16
Our series
8, M
Ophthalmoplegia, exotropia
None
Cav
R
5.5 5 4
SRT
56
Unchanged CN III palsy
No
10, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis-Cav
R
11 5 8
SRT
58
Unchanged CN III palsy
No
Tumor location: cisternal (Cis) versus cavernous (Cav) versus cisternocavernous (Cis-Cav). L, left; R, right; CN, cranial nerve; M, male; ND, not described; F, female; SRT, stereotactic radiotherapy.
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2, F
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Follow-Up, months
Treatment
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Table 1. Characteristics of Pediatric Patients With Oculomotor Schwannoma Reported in the Literature
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Table 2. Characteristics of Patients With Oculomotor Schwannomas Treated With Stereotactic Radiotherapy or Stereotactic Radiosurgery
Author, Year
Age, Sex
Pre-Irradiation Symptoms
Prior Resection (Time Prior)
Tumor Side Location (L/R)
Tumor Volume, cm3
Treatment
Margin dose/ Dose/ Maximum Fraction, Total Dose, Gy Gy/Frac Dose, Gy
FollowUp, months
Posttreatment CN III Status NF II
LINAC FSRT
25
125
18
Improved
No
GKS
13.5*/30*
37,y 54*
ND
ND
Abo-Shasha et al., 201827
49
Headache, mydriasis, ptosis, ophthalmoplegia
No
Elsharkawy et al., 201228
48*
ND
ND
29, M
Ptosis
Yes, 3 years
ND
ND
7.4
GKS
11/ND
9
No change
No
19, F
Ophthalmoplegia
No
Cisternal
Left
0.07
GKS
13/ND
36
No change
No
ND
ND
ND
ND
ND
5.3*
LINAC SRS
12.5/ND
19*
ND
No
ND
ND
5.3*
LINAC SRS
12.5/ND
19*
ND
No
Cavernous Left
22.5
Subtotal Resection þ LINAC FSRT
2
54
ND
ND
No
29
Kim et al., 2008
Kimball et al., 201130
Cavernous Right ND (4 mm diam)
ND
ND
ND
29
Headache, diplopia, Visual loss, ophthalmoplegia
Yes, 2 years
Nishioka et al., 200932
ND
ND
Yes, 7.3 years*
Saetia et al., 201133
41
Showalter et al., 200834
ND
Ptosis
No
ND
ND
Ptosis
No
ND
2.9*
ND
8.2y
FSRT (ND)
2
50*
59.5*
ND
No
Visual loss, complete Yes, 5 months Cavernous Left CNII palsy
5.4
Cyberknife FSRT
ND
7
Complete palsy
No
ND
6.5,y 4.2*
ND
ND
ND
ND
24*
ND
ND
ND
6.5,y 4.2*
ND
ND
ND
ND
24*
ND
ND
ND
L, left; R, right; CN, cranial nerve; NF, neurofibromatosis; ND, not described; LINAC, linear accelerator; FSRT, fractionated stereotactic radiotherapy; GKS, Gamma knife radiosurgery; M, male; F, female; SRS, stereotactic radiosurgery. *Median value. yMean value.
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ND Kumar et al., 201431
Right
LITERATURE REVIEW HASSAN A. FADEL ET AL.
These results were replicated in the literature, most notably in a larger study by Nishioka et al., in which 17 patients with schwannomas of the jugular foramen (n ¼ 7), trigeminal nerve (n ¼ 5), facial nerve (n ¼ 4), and oculomotor nerve (n ¼ 1) were treated with either primary (n ¼ 10) or postsurgical (n ¼ 7) fractionated radiotherapy.32,34 Using a median total dose of 50 Gy over 25 fractions targeting a median tumor volume of 8.7 cm3, tumor control was achieved in 94% of patients on median follow-up of 59.5 months, with no patients experiencing a worsening of symptoms or the development of new CN deficits. It should be noted that a common theme in the existing literature regarding oculomotor schwannomas is that reported cases tend to be part of larger clinical cohorts of nonvestibular schwannomas. Such cohorts are made up of far more patients with other nonvestibular schwannomas and fail to include or make a distinction of data for individual cases of oculomotor schwannomas. The use of fractionated Cyberknife SRT for adult oculomotor schwannoma has only been reported once in the literature to date. Saetia et al.33 described the case of a 41-year-old patient with oculomotor schwannoma who underwent subtotal resection resulting in tumor recurrence 4 months following resection. The recurrent tumor was then treated with fractionated Cyberknife SRT; however, details of the dosage and fractionation regimen were not reported. Traditionally, fractionated radiotherapy without stereotactic immobilization, targeting, and beam guidance requires a setup error of 4e5 mm. This set-up error decreases the conformality of the dosing and increases the dose delivered to surrounding structures. In the case of the oculomotor nerve, the adjacent structures of concern include the optic apparatus and the mesial temporal structures. This lack of conformality increases the risk of delayed radiation effects such as optic neuropathy, neurocognitive decline, and development of secondary malignancies.55 In contrast, the Cyberknife (Accuray, Inc.) is a stereotactic linear accelerator radiation source mounted to a robot arm, which tracks patient movement in near real time as the treatment is delivered. As such, the set-up error is reduced or
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eliminated. It has been shown to have a similar dose conformality to Gammaknife radiosurgery with similar tumor control rates in multiple pathologies.56 Cyberknife (Accuray, Inc.), however, has the benefit of not requiring a stereotactic frame to be placed because of the sophisticated ongoing image guidance. This can be of particular benefit in the pediatric population, as it spares the morbidity of head frame placement allowing protracted fractionation. With the highly conformal dose distribution and the fractionation scheme, Cyberknife (Accuray, Inc.) combines the benefits of SRS with traditional fractionation. In the pediatric population, the greatest concern for delivering radiation to a benign disease process are the delayed effects of radiation (e.g., neurocognitive effects and secondary malignancy). Fractionated Cyberknife (Accuray, Inc.) SRT has theoretical benefit over traditionally fractionated external beam radiotherapy by using marginless treatment to limit the exposure of surrounding structures to high-dose radiation. Therefore, Fractionated Cyberknife (Accuray, Inc.) SRT theoretically diminishes the risk of neurocognitive decline, optic neuropathy, and secondary malignancy that may be associated with high-dose radiation to oculomotor schwannomas. This is accomplished, however, by a trade-off of larger volumes of low-dose exposure, which, while not associated with focal neurologic deficits, may be associated with global neurocognitive problems and out-of-field secondary cancer. As such, long-term follow-up is required. Our 2 patients are the first described cases of oculomotor nerve schwannomas to be treated with traditionally fractionated Cyberknife (Accuray, Inc.) SRT. Both of our patients, who were treated with 45e50 Gy administered over 25 fractions, achieved long-term tumor control with no symptomatic progression, no treatment complications, and no cognitive deficits at nearly 5-year follow-up (1 patient demonstrated a radiologic decrease in tumor volume at 30 months). The clinical and radiologic results achieved with fractionated Cyberknife (Accuray, Inc.) SRT stand in stark contrast to the morbidity and possible tumor recurrence experienced in microsurgical patients.
Limitations All studies included in this systematic review were case series or case reports, which are limited by small sample size and selection bias. This is an inherent limitation of retrospective review of the literature. Due to the rarity of the disease, it would be difficult to test our treatment paradigm on a large cohort of patients. However, our case illustrations and reported outcome show that fractionated Cyberknife (Accuray, Inc.) SRT can be considered in select cases of oculomotor schwannomas. CONCLUSIONS The success of our reported treatment paradigm provides novel approach to be added to the armamentarium of treatment options for these incredibly rare and debilitating tumors in the pediatric population. Long-term follow-up is required to better quantify late effects of this approach. REFERENCES 1. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011e2015. Neuro Oncol. 2018;20(suppl_4):iv1-iv86. 2. Konovalov AN, Spallone A, Mukhamedjanov DJ, Tcherekajev VA, Makhmudov UB. Trigeminal neurinomas. A series of 111 surgical cases from a single institution. Acta Neurochir. 1996;138: 1027-1035. 3. Samii M, Migliori MM, Tatagiba M, Babu R. Surgical treatment of trigeminal schwannomas. J Neurosurg. 1995;82:711-718. 4. Sarma S, Sekhar LN, Schessel DA, Malis LI, Day JD. Nonvestibular schwannomas of the brain: a 7-year experience. Neurosurgery. 2002;50:437-449. 5. Tan LC, Bordi L, Symon L, Cheesman AD. Jugular foramen neuromas: a review of 14 cases. Surg Neurol. 1990;34:205-211. 6. Kida Y, Yoshimoto M, Hasegawa T. Radiosurgery for facial schwannoma. J Neurosurg. 2007;106: 24-29. 7. Symon L, Cheesman AD, Kawauchi M, Bordi L. Neuromas of the facial nerve: a report of 12 cases. Br J Neurosurg. 1993;7:13-22. 8. Plitt A, El Ahmadieh TY, Bindal S, Myers L, White J, Gluf W. Hypoglossal schwannoma of neck: case report and review of literature. World Neurosurg. 2018;110:240-243.
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9. Bindal S, El Ahmadieh TY, Plitt A, et al. Hypoglossal schwannomas: a systematic review of the literature. J Clin Neurosci. 2019;62:162-173. 10. Kansu T, Özcan OE, Özdirim E, Önol B, Gürcay Ö. Neurinoma of the oculomotor nerve. J Clin Neuroophthalmol. 1982;2:271-272. 11. Leunda G, Vaquero J, Cabezudo J, Garcia-Uria J, Bravo G. Schwannoma of the oculomotor nerves. Report of four cases. J Neurosurg. 1982;57:563-565. 12. Niazi W, Boggan JE. Schwannoma of extraocular nerves: survey of literature and case report of an isolated third nerve schwannoma. Skull Base Surg. 1994;4:219-226. 13. Bejjani GK, Duong DH, Kalamarides M, Ziyal I, Sullivan BJ. Cerebral vasospasm after tumor resection. A case report. Neurochirurgie. 1997;43: 164-168. 14. Mariniello G, Horvat A, Dolenc VV. En bloc resection of an intracavernous oculomotor nerve schwannoma and grafting of the oculomotor nerve with sural nerve. Case report and review of the literature. J Neurosurg. 1999;91:1045-1049. 15. Norman AA, Farris BK, Siatkowski RM. Neuroma as a cause of oculomotor palsy in infancy and early childhood. J AAPOS. 2001;5:9-12. 16. Netuka D, Benes V. Oculomotor nerve schwannoma. Br J Neurosurg. 2003;17:168-173. 17. Murakami T, Funatsuka M, Komine M, et al. Oculomotor nerve schwannoma mimicking ophthalmoplegic migraine. Neuropediatrics. 2005;36: 395-398. 18. Bisdorff A, Wildanger G. Oculomotor nerve schwannoma mimicking ophthalmoplegic migraine. Cephalalgia. 2006;26:1157-1159. 19. Chewning RH, Sasson AD, Jordan LC, Tamargo RJ, Gailloud P. Acute third cranial nerve palsy from a third cranial nerve schwannoma presenting as a saccular aneurysm on threedimensional computed tomography angiography: case illustration. J Neurosurg. 2008;108:1037.
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25. Peciu-Florianu I, Tuleasca C, Comps J-N, et al. Radiosurgery in trochlear and abducens nerve schwannomas: case series and systematic review. Acta Neurochir. 2017;159:2409-2418.
39. Iijima K, Tosaka M, Nagano T, et al. Oculomotor nerve schwannoma associated with acute hydrocephalus: case report. Neurol Med Chir (Tokyo). 2014;54:654-658.
26. Nonaka Y, Fukushima T, Friedman AH, Kolb LE, Bulsara KR. Surgical management of nonvascular lesions around the oculomotor nerve and reconstruction of the oculomotor nerve. World Neurosurg. 2014;81:798-809.
40. Furtado SV, Hegde AS. Management of oculomotor nerve schwannomas in two different locations: surgical nuances and comprehensive review. Neurosurg Rev. 2012;35:27-34.
27. Abo-Shasha R, Bauman GS, Fraser JA. Stereotactic radiotherapy for presumed oculomotor nerve schwannoma masquerading as “ophthalmoplegic migraine”. Can J Ophthalmol. 2018;53:e167-e168. 28. Elsharkawy M, Xu Z, Schlesinger D, Sheehan JP. Gamma Knife surgery for nonvestibular schwannomas: radiological and clinical outcomes. J Neurosurg. 2012;116:66-72. 29. Kim I-Y, Kondziolka D, Niranjan A, Flickinger JC, Lunsford LD. Gamma Knife surgery for schwannomas originating from cranial nerves III, IV, and VI. J Neurosurg. 2008;109(suppl):149-153. 30. Kimball MM, Foote KD, Bova FJ, Chi Y-Y, Friedman WA. Linear accelerator radiosurgery for nonvestibular schwannomas. Neurosurgery. 2011; 68:974-984. 31. Kumar LP, Monica I, Uppin MS, Kotiyala VJ. Large oculomotor nerve schwannoma—rare entity: a case report with review of literature. J Cancer Res Ther. 2014;10:1098-1100. 32. Nishioka K, Abo D, Aoyama H, et al. Stereotactic radiotherapy for intracranial nonacoustic schwannomas including facial nerve schwannoma. Int J Radiat Oncol Biol Phys. 2009;75: 1415-1419. 33. Saetia K, Larbcharoensub N, Wetchagama N. Oculomotor nerve schwannoma: a case report and review of the literature. J Med Assoc Thai. 2011;94: 1002-1007.
41. Pollock BE, Foote RL, Stafford SL. Stereotactic radiosurgery: the preferred management for patients with nonvestibular schwannomas? Int J Radiat Oncol Biol Phys. 2002;52:1002-1007. 42. Huang C-F, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for trigeminal schwannomas. Neurosurgery. 1999;45: 11-15. 43. Martin JJ, Kondziolka D, Flickinger JC, Mathieu D, Niranjan A, Lunsford LD. Cranial nerve preservation and outcomes after stereotactic radiosurgery for jugular foramen schwannomas. Neurosurgery. 2007;61:76-81. 44. Hasegawa T, Kida Y, Yoshimoto M, Koike J. Trigeminal schwannomas: results of gamma knife surgery in 37 cases. J Neurosurg. 2007;106:18-23. 45. Zabel A, Debus J, Thilmann C, Schlegel W, Wannenmacher M. Management of benign cranial nonacoustic schwannomas by fractionated stereotactic radiotherapy. Int J Cancer. 2001;96: 356-362. 46. Pan L, Wang E-M, Zhang N, et al. Long-term results of Leksell gamma knife surgery for trigeminal schwannomas. J Neurosurg. 2005; 102(Special_Supplement):220. 47. Langlois A-M, Iorio-Morin C, Masson-Côté L, Mathieu D. Gamma knife stereotactic radiosurgery for nonvestibular cranial nerve schwannomas. World Neurosurg. 2018;110:e1031-e1039. 48. Persson O, Bartek J, Shalom NB, Wangerid T, Jakola AS, Förander P. Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review. Acta Neurochir. 2017;159:1013-1021.
20. Goel A, Shah A. “Interdural” oculomotor neurinoma: report of two surgically treated cases. Acta Neurochir. 2010;152:1721-1724.
34. Showalter TN, Werner-Wasik M, Curran WJ, Friedman DP, Xu X, Andrews DW. Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of nonacoustic cranial nerve schwannomas. Neurosurgery. 2008;63: 734-740.
21. Yang S-S, Li Z-J, Liu X, Li Y, Li S-F, Zhang H-D. Pediatric isolated oculomotor nerve schwannoma: a new case report and literature review. Pediatr Neurol. 2013;48:321-324.
35. Leber KA, Berglöff J, Pendl G. Doseresponse tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg. 1998;88:43.
49. Aoyama H, Onodera S, Takeichi N, et al. Symptomatic outcomes in relation to tumor expansion after fractionated stereotactic radiation therapy for vestibular schwannomas: single-institutional long-term experience. Int J Radiat Oncol Biol Phys. 2013;85:329-334.
22. Mariniello G, de Divitiis O, Caranci F, Dones F, Maiuri F. Parasellar schwannomas: extradural vs extra-intradural surgical approach. Oper Neurosurg (Hagerstown). 2018;14:627-638.
36. Purdy JA. Dose to normal tissues outside the radiation therapy patient’s treated volume: a review of different radiation therapy techniques. Health Phys. 2008;95:666-676.
50. Litre F, Rousseaux P, Jovenin N, et al. Fractionated stereotactic radiotherapy for acoustic neuromas: a prospective monocenter study of about 158 cases. Radiother Oncol. 2013;106:169-174.
23. Lee D, Kim WJ, Kim MM. Recurrent isolated oculomotor nerve palsy caused by schwannoma in a pediatric patient. Indian J Ophthalmol. 2018;66: 1367-1369.
37. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336-341.
51. Thomas C, Maio SD, Ma R, et al. Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: prognostic implications of cochlear dose. J Neurosurg. 2007; 107:917.
24. Celli P, Ferrante L, Acqui M, Mastronardi L, Fortuna A, Palma L. Neurinoma of the third, fourth, and sixth cranial nerves: a survey and report of a new fourth nerve case. Surg Neurol. 1992;38:216-224.
38. Safavi-Abbasi S, Bambakidis NC, Zabramski JM, et al. Nonvestibular schwannomas: an evaluation of functional outcome after radiosurgical and microsurgical management. Acta Neurochir. 2010; 152:35-46.
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52. Apicella G, Paolini M, Deantonio L, Masini L, Krengli M. Radiotherapy for vestibular schwannoma: review of recent literature results. Rep Pract Oncol Radiother. 2016;21:399-406.
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53. Combs SE, Engelhard C, Kopp C, et al. Long-term outcome after highly advanced single-dose or fractionated radiotherapy in patients with vestibular schwannomas—pooled results from 3 large German centers. Radiother Oncol. 2015;114:378-383. 54. Toshinori H, Yoshihisa K, Takenori K, Hiroshi I, Shunichiro K, Takashi Y. Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas: evaluation of 440 patients more than 10 years after treatment with Gamma Knife surgery. J Neurosurg. 2013;118:557-565. 55. Marchetti M, Bianchi S, Milanesi I, et al. Multisession radiosurgery for optic nerve sheath
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meningiomas—an effective option: preliminary results of a single-center experience. Neurosurgery. 2011;69:1116-1122 [discussion: 1122-1123]. 56. Collins SP, Coppa ND, Zhang Y, et al. CyberKnife radiosurgery in the treatment of complex skull base tumors: analysis of treatment planning parameters. Radiat Oncol. 2006;1:46.
Received 16 March 2019; accepted 13 May 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.05.114 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Oculomotor Schwannomas: A Systematic Review and Report of Two Pediatric Cases Treated with Fractionated Cyberknife Stereotactic Radiotherapy Hassan A. Fadel1, Tarek Y. El Ahmadieh2, Aaron R. Plitt2, Om J. Neeley2, Zachary Johnson2, Salah G. Aoun2, Osama Mohamad3, Robert Timmerman2,3, Bradley E. Weprin2,3
Key words Cyberknife - Fractionated radiotherapy - Oculomotor - Pediatric - Schwannoma -
Abbreviations and Acronyms CN: Cranial nerve MRI: Magnetic resonance imaging SRS: Stereotactic radiosurgery SRT: Stereotactic radiotherapy From the 1Wayne State University School of Medicine, Detroit, Michigan; and Departments of 2Neurological Surgery, and 3Radiation Oncology, University of Texas Southwestern, Dallas, Texas, USA To whom correspondence should be addressed: Tarek Y. El Ahmadieh, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.05.114 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Schwannomas are benign peripheral nerve sheath tumors that represent approximately 9% of all primary central nervous system tumors. They originate from the vestibular nerve in 95.5% of cases.1 Nonvestibular intracranial schwannomas commonly arise from the cranial nerves (CNs) traversing the jugular foramen (CN IX, X, and XI), the facial nerve (CN VII), the trigeminal nerve (CN V), or the hypoglossal nerve (CN XII).2-9 Schwannomas of the oculomotor nerve (CN III) are extremely rare, particularly in the pediatric population.10-23 Depending on their location and pattern of growth, oculomotor schwannomas are classified as cisternal, cisternocavernous, or cavernous, with presenting symptoms varying from incomplete oculomotor palsy to clinical sequalae of brainstem compression.24,25 Because of the variability in tumor location, tumor size, and presenting features, the treatment of
- OBJECTIVE:
Pediatric oculomotor nerve schwannomas are rare and challenging lesions due to the high morbidity associated with surgical intervention and their proximity to critical structures limiting the opportunity for stereotactic radiosurgery. We aim to report and review the novel use of fractionated Cyberknife (Accuray, Inc., Sunnyvale, California, USA) stereotactic radiotherapy in pediatric patients with oculomotor schwannomas.
- METHODS:
A systematic review of PubMed, Embase, and Cochrane was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two patients, ages 8 and 10 years, with tumor volumes of 0.1 cm3 and 0.2 cm3, respectively, were treated with fractionated Cyberknife radiotherapy at our institution. A total dose of 45e50 Gy was administered over 25 fractions (1.8e2.0 Gy per fraction) to the 82%L84% isodose line. Serial magnetic resonance imaging was obtained for long-term follow-up (56e58 months).
- RESULTS:
We found 14 articles published between 1982 and 2018 that reported a total of 18 pediatric patients with intracranial oculomotor schwannomas. No previously described cases of pediatric intracranial oculomotor schwannomas were treated with radiation therapy. In both of our patients, radiographic tumor control was achieved at a mean follow-up of 57 months, with 1 patient displaying a decrease in tumor volume. Neither patient exhibited any worsening of their presenting symptoms, nor did either patient develop any new neurocognitive deficits following treatment.
- CONCLUSIONS:
Fractionated Cyberknife radiotherapy is an effective and well-tolerated treatment option for intracranial oculomotor nerve schwannomas with excellent tumor control rates, similar to surgical and radiosurgical techniques, while sparing critical surrounding structures.
pediatric or adult oculomotor schwannomas often is multimodal and includes medical therapy, microsurgical resection, and/or primary or adjunct irradiation. Historically, the standard treatment for nonvestibular schwannomas, including oculomotor schwannomas, has been microsurgical resection. However, this treatment modality has been associated with a relatively high tumor recurrence rate requiring retreatment, as well as a high rate of postsurgical complications and neurologic morbidity.11,13,14,17,20,21,26 Despite recent advances in microsurgical techniques and the development of novel skull base approaches, surgical resection
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of oculomotor schwannomas remains a challenging treatment option that carries invariable risk of diplopia. Stereotactic radiotherapy (SRT) is typically used for unresectable lesions as well as recurrent and residual disease.27-34 Although stereotactic radiosurgery (SRS) has been shown to be effective in targeting other nonvestibular schwannomas, there is limited utility of SRS for lesions of the oculomotor nerve due to the proximity of the optic apparatus that exhibits a high sensitivity to single-fraction radiation (8e10 Gy).35 Conversely, fractionated SRT can be used to target such lesions, as the surrounding optic apparatus has been
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Figure 1. Flow diagram according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement describing the identification,
shown to have a fractionated dose tolerance of 55e60 Gy.36 Therefore, the novel treatment paradigm of fractionated Cyberknife (Accuray, Inc., Sunnyvale, California, USA) SRT combines the dose conformality of SRS with the benefits of fractionation to deliver a highly conformal dose to the target lesion that spares critical surrounding structures. In the following report, we present the clinical course and outcome of 2 pediatric patients with oculomotor schwannomas treated with fractionated Cyberknife (Accuray, Inc.) SRT. These are the first reported cases of oculomotor nerve schwannomas treated with fractionated Cyberknife SRT in the pediatric population. We complement our report with a systematic review of the literature for these extremely rare tumors.
screening, exclusion and inclusion of studies reporting oculomotor schwannomas in pediatric patients.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to collect all cases of pediatric oculomotor schwannomas treated medically, surgically, and/or with primary or adjuvant SRT or SRS.37 A combination of the following key search terms was used to identify all relevant studies: “pediatric,” “oculomotor,” “schwannoma,” “neurilemmoma,” “radiotherapy,” and “radiosurgery.” The primary search was supplemented with a hand-review of the reference sections of all relevant manuscripts. The search was restricted to peer-reviewed studies published in the English language (Figure 1). Assessment of risk of bias across studies was not conducted, given all included articles were observational studies or case reports, for which there is no validated tool for risk of bias assessment.
METHODS Literature Review A systematic review of PubMed, Embase, and Cochrane was completed according to
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CASE DESCRIPTIONS Two recent pediatric patients have been diagnosed with oculomotor schwannomas
and treated with fractionated Cyberknife (Accuray, Inc.) SRT at our institution. Case 1 Our first patient was a 10-year-old female patient at the time of her initial presentation. She had a history of obesity and dyslipidemia and presented with headaches and a right-sided partial third nerve (CN III) palsy. Her CN III palsy evolved over 18 months, with diplopia developing 4 months before presentation. Her headaches were chronic in nature. Magnetic resonance imaging (MRI) of the brain was completed and revealed an 11 5 8 mm (anteroposterior transverse craniocaudal) enhancing mass intimately associated with the cisternal segment of the right-sided third CN with extension into the right cavernous sinus (Figure 2). Formal ophthalmologic evaluation revealed full visual fields with right-sided ptosis and inferior and medial recti weakness. Following discussion in multidisciplinary tumor conference, treatment
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Figure 2. Axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging obtained in a 10-year-old female patient demonstrating an 11-mm anteroposterior 5-mm transverse 8-mm
with fractionated Cyberknife (Accuray, Inc.) SRT was recommended. Between July and August 2012, a total of 45 Gy was administered over 25 fractions (1.8 Gy per fraction) to a gross total volume of 0.46 cm3. The dose was delivered to the 82% isodose line with 96.5% target coverage. Importantly, the maximum optic pathway dose was 34.8 Gy. Follow up MRIs were obtained at 6, 12, 18, 30, 42, and 58 months. The mass exhibited a slight
craniocaudal contrast-enhancing mass involving the cisternal segment of the right oculomotor nerve with protrusion into the right cavernous sinus.
decrease in size at 30 months with stable imaging thereafter (Figure 3). Formal post-treatment ophthalmologic testing was completed every 6 months for the first 18 months followed by annual examinations thereafter. Throughout follow-up, the patient did not develop a new visual field deficit, diminution in visual acuity, or worsening of her pretreatment diplopia. She eventually underwent strabismus correction surgery 15 months after
Figure 3. Five-year follow-up axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging demonstrating stable fusiform enhancing mass
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completion of radiation therapy with subsequent resolution of her diplopia. She is currently being monitored with biannual MRI examinations and continues to follow up with oncology and ophthalmology. Case 2 Our second patient was an 8-year-old male patient at the time of his initial presentation. He presented with alternating exotropia and a right-sided CN III palsy
involving the cisternal segment of the right oculomotor nerve.
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Figure 4. Axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging obtained in an 8-year-old male patient demonstrating a 5.5-mm AP 5-mm transverse 4-mm contrast-enhancing
(ptosis) over a 2-week timeframe. An MRI of the brain revealed a 5.5 5 4 mm (anteroposterior transverse craniocaudal) enhancing lesion intimately involved with the right third CN within the cavernous sinus (Figure 4). Multidisciplinary consensus was again to treat with fractionated Cyberknife (Accuray, Inc.) SRT. Between August and September 2013, a total of 50 Gy was administered over 25 fractions (2 Gy per fraction) to a gross total volume of 0.299 cm3 (Figure 5). The dose was delivered to the 84% isodose line with 99.8% target coverage. The maximum optic pathway dose was 16.5 Gy. Due to persistent post-treatment
diplopia, the patient subsequently underwent right-sided strabismus correction surgery and ptosis repair 12 months after completion of radiation therapy. His diplopia improved over the ensuing 12 months, with continued stable ophthalmologic examinations performed at 6month intervals. His CN III palsy has remained unchanged throughout the post-treatment period. Follow-up MRIs were obtained at 6, 12, 24, 36, and 56 months, with the mass exhibiting no change in size on serial imaging (Figure 6). He is currently being monitored with biannual MRI and continues to follow up with oncology and ophthalmology.
Figure 5. CyberKnife treatment plan for a right oculomotor nerve schwannoma showing the target and nearby organs at risk (brain stem in pink, pituitary in yellow, right and left optic nerves in teal and
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mass in the right cavernous sinus along the course of the right oculomotor nerve. Arrows denote contrast enhancing oculomotor schwannoma.
RESULTS In our systematic review of the literature, we found 14 articles published between 1982 and 2018 reporting a total of 18 pediatric patients with intracranial oculomotor schwannomas (Table 1).10-23 Due to the extreme rarity of oculomotor schwannomas, particularly in the pediatric population, all but 2 published studies are isolated case reports, with 1 case series of 5 patients. Presenting symptoms for pediatric patients with oculomotor schwannomas included ophthalmoplegia (94%), ptosis (61%), headache (50%), and diplopia (33%) (Table 1). Including our patients, the age at presentation ranged between 2 months and
green, and carotid arteries in red). The patient received 50 Gy in 25 fractions. Representative isodose lines are also shown in the axial (A), sagittal (B), and coronal (C) views.
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Figure 6. Five-year follow-up axial (A) and coronal (B) T1-weighted postcontrast magnetic resonance imaging
16 years (mean age of 8 years), with a 12:8 female predominance. Maximal tumor diameters were documented between 1.7 mm and 55 mm (mean diameter of 17.2 mm). The majority of reported pediatric oculomotor schwannomas (10 patients) were treated with total or partial microsurgical resection, whereas 2 patients were treated medically. The method of treatment for 6 patients was not described. Of the 18 previously reported cases of pediatric oculomotor schwannomas, none were treated with radiotherapy. DISCUSSION Microsurgical resection has historically stood as the standard primary treatment modality for pediatric intracranial oculomotor schwannomas.10-14,16,17,20-22 However, microsurgical resection has been associated with a high morbidity rate and the added rare risk of postsurgical complications such as infection, cerebrospinal fluid leak, hydrocephalus, and vasospasm leading to hemiparesis.4,11,13,14,16,17,21,28,32,38 Namely, the improvement and preservation of the oculomotor nerve function has proven to be challenging. Postoperative oculomotor nerve functional improvement has been reported in 11% of patients, with 50% of patients experiencing postoperative functional decline as well as aberrant nerve regeneration.4,14,26,39,40 Furthermore, tumor recurrence of nonvestibular schwannomas
demonstrating stable enhancing lesion within the right cavernous sinus.
following microsurgical resection has been reported to be as high as 17% at 12- to 60month follow-up (25 month mean), with numerous cases of recurrent oculomotor schwannomas requiring retreatment noted in the literature.3,26,28,29,31,32 To date, 10 pediatric patients with oculomotor schwannomas have been treated with microsurgical resection.10-14,16,17,20-22 Of these 10 patients, only 2 experienced postoperative improvement in oculomotor nerve function, one of which was following a subtotal resection complicated by tumor recurrence necessitating re-operation.12,22 Despite the use of careful dissection and graft reconstruction following microsurgery, 6 surgically treated pediatric patients experienced worsening of oculomotor nerve function on long-term follow-up (2e240 months).11,13,14,16,17,21 Fractionated radiotherapy for nonvestibular schwannomas has been shown to achieve excellent tumor control with marginal adverse side effects in adults. Table 2 summarizes all adult cases of oculomotor schwannomas treated with SRT or SRS reported in the literature to date.27-33,41-45 The favorable use of SRS in the treatment of 23 patients with nonvestibular schwannomas (trigeminal [n ¼ 10], jugular foramen [n ¼ 10], hypoglossal [n ¼ 2], and trochlear [n ¼ 1] schwannomas), but not oculomotor schwannomas, was reported by Pollock et al.41 Using a median dose of 18 Gy (12e20 Gy) to target 23 tumors ranging between 0.2 and 17.6 cm3 (8.9
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cm3 mean) in size, local tumor control was achieved in 96% of patients on longterm follow-up (12e111 months), with new neurologic deficits occurring in 3 patients. More recent series using SRS as the primary or adjuvant treatment of nonvestibular schwannomas, including oculomotor schwannomas, have replicated and improved on those results described by Pollock et al., while using lower doses of radiation (Table 2).6,25,28-30,44,46,47 Fractionated radiotherapy (i.e., 25e30 fractions) has proven to be an effective treatment for both vestibular and nonvestibular intracranial schwannomas.32,45,48-50 Targeting vestibular schwannomas with a dose of 45e50 Gy delivered over 25 fractions has been shown to achieve high tumor control rates (>95%) on long-term follow-up as well as progression-free survival rates on par with those of microsurgical resection, while also exhibiting minimal toxic effects.48-54 Zabel et al.45 was the first to report the results of linear accelerator fractionated radiotherapy in 13 adult patients with nonvestibular intracranial schwannomas, including 3 patients with oculomotor schwannomas. The study found that a median dose of 57.6 Gy with 1.8 Gy per fraction targeting a median tumor volume of 19.8 cm3 led to a 100% tumor control rate without any patient developing CN or brainstem deficits on long-term follow-up (median 33 months).
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Age, years, Sex
Presenting Signs and Symptoms
Previous Treatment
Tumor Location
Side (L/R)
Tumor Size, mm
Kansu et al., 198210
15, M
Ophthalmoplegia, ptosis, mydriasis
None
Cis
R
4
Leunda et al., 198211
11, M
Headaches, hemiparesis, ophthalmoplegia
None
ND
L
Niazi and Boggan, 199412
13, M
Headaches, hemiparesis, diplopia, ptosis, anisocoria
None
Cis-cav
Bejjani et al., 199713
6, F
Ophthalmoplegia, diplopia
None
Mariniello et al., 199914
8, F
Ophthalmoplegia, ptosis, exotropia
2 months, M
Ophthalmoplegia, ptosis, anisocoria
2 months, M
Ophthalmoplegia, Anisocoria
None
Cis
L
8 months, F
Anisocoria
None
Cav
R
Study
Norman et al., 200115
Posttreatment CN III Status
Re-Treatment
Gross total resection
ND
ND
ND
55
Gross total resection
108
Worsened CN III palsy
No
R
50
Subtotal resection
111
Improved CN III palsy Resection of recurrent tumor
Cis
R
12
Subtotal resection
4
Worsened CN III palsy
No
None
Cav
L
10
Gross total resection
24
Worsened CN III palsy
No
None
Cav
R
3
ND
7
ND
ND
ND
Ophthalmoplegia, ptosis
None
Cis
L
ND
ND
3, F
Ophthalmoplegia, exotropia
None
Cav
R
ND
ND
Netuka et al., 2003
12, F
Headaches
None
Cis-Cav
L
28
Gross total resection
12
Worsened CN III palsy
No
Murakami et al., 200517
11, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis
L
5
Gross total resection
2
Worsened CN III palsy
No
Bisdorff and Wildanger, 200618
14, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis
R
7
Medical management
Chewning et al., 200819
3, F
Headaches, ophthalmoplegia, anisocoria
None
Cis
R
4
ND
Goel and Shah, 201020
16, M
Headaches, ophthalmoplegia, ptosis
None
Cav
L
53
Gross total resection
24
Unchanged CN III palsy
No
Yang et al., 201321
3, M
Ophthalmoplegia, ptosis
None
Cis
R
11 12 13
Gross total resection
12
Worsened CN III palsy
No
Mariniello et al., 201722
16, F
Ophthalmoplegia, exotropia
None
Cis-Cav
L
1.7 1.5 1.2
Gross total resection
240
Improved CN III palsy
No
Lee et al., 201823
10, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis
R
6
Medical management
16
Our series
8, M
Ophthalmoplegia, exotropia
None
Cav
R
5.5 5 4
SRT
56
Unchanged CN III palsy
No
10, F
Headaches, ophthalmoplegia, ptosis, diplopia
None
Cis-Cav
R
11 5 8
SRT
58
Unchanged CN III palsy
No
Tumor location: cisternal (Cis) versus cavernous (Cav) versus cisternocavernous (Cis-Cav). L, left; R, right; CN, cranial nerve; M, male; ND, not described; F, female; SRT, stereotactic radiotherapy.
LITERATURE REVIEW
2, F
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Follow-Up, months
Treatment
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Table 1. Characteristics of Pediatric Patients With Oculomotor Schwannoma Reported in the Literature
HASSAN A. FADEL ET AL.
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Table 2. Characteristics of Patients With Oculomotor Schwannomas Treated With Stereotactic Radiotherapy or Stereotactic Radiosurgery
Author, Year
Age, Sex
Pre-Irradiation Symptoms
Prior Resection (Time Prior)
Tumor Side Location (L/R)
Tumor Volume, cm3
Treatment
Margin dose/ Dose/ Maximum Fraction, Total Dose, Gy Gy/Frac Dose, Gy
FollowUp, months
Posttreatment CN III Status NF II
LINAC FSRT
25
125
18
Improved
No
GKS
13.5*/30*
37,y 54*
ND
ND
Abo-Shasha et al., 201827
49
Headache, mydriasis, ptosis, ophthalmoplegia
No
Elsharkawy et al., 201228
48*
ND
ND
29, M
Ptosis
Yes, 3 years
ND
ND
7.4
GKS
11/ND
9
No change
No
19, F
Ophthalmoplegia
No
Cisternal
Left
0.07
GKS
13/ND
36
No change
No
ND
ND
ND
ND
ND
5.3*
LINAC SRS
12.5/ND
19*
ND
No
ND
ND
5.3*
LINAC SRS
12.5/ND
19*
ND
No
Cavernous Left
22.5
Subtotal Resection þ LINAC FSRT
2
54
ND
ND
No
29
Kim et al., 2008
Kimball et al., 201130
Cavernous Right ND (4 mm diam)
ND
ND
ND
29
Headache, diplopia, Visual loss, ophthalmoplegia
Yes, 2 years
Nishioka et al., 200932
ND
ND
Yes, 7.3 years*
Saetia et al., 201133
41
Showalter et al., 200834
ND
Ptosis
No
ND
ND
Ptosis
No
ND
2.9*
ND
8.2y
FSRT (ND)
2
50*
59.5*
ND
No
Visual loss, complete Yes, 5 months Cavernous Left CNII palsy
5.4
Cyberknife FSRT
ND
7
Complete palsy
No
ND
6.5,y 4.2*
ND
ND
ND
ND
24*
ND
ND
ND
6.5,y 4.2*
ND
ND
ND
ND
24*
ND
ND
ND
L, left; R, right; CN, cranial nerve; NF, neurofibromatosis; ND, not described; LINAC, linear accelerator; FSRT, fractionated stereotactic radiotherapy; GKS, Gamma knife radiosurgery; M, male; F, female; SRS, stereotactic radiosurgery. *Median value. yMean value.
LITERATURE REVIEW
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ND Kumar et al., 201431
Right
LITERATURE REVIEW HASSAN A. FADEL ET AL.
These results were replicated in the literature, most notably in a larger study by Nishioka et al., in which 17 patients with schwannomas of the jugular foramen (n ¼ 7), trigeminal nerve (n ¼ 5), facial nerve (n ¼ 4), and oculomotor nerve (n ¼ 1) were treated with either primary (n ¼ 10) or postsurgical (n ¼ 7) fractionated radiotherapy.32,34 Using a median total dose of 50 Gy over 25 fractions targeting a median tumor volume of 8.7 cm3, tumor control was achieved in 94% of patients on median follow-up of 59.5 months, with no patients experiencing a worsening of symptoms or the development of new CN deficits. It should be noted that a common theme in the existing literature regarding oculomotor schwannomas is that reported cases tend to be part of larger clinical cohorts of nonvestibular schwannomas. Such cohorts are made up of far more patients with other nonvestibular schwannomas and fail to include or make a distinction of data for individual cases of oculomotor schwannomas. The use of fractionated Cyberknife SRT for adult oculomotor schwannoma has only been reported once in the literature to date. Saetia et al.33 described the case of a 41-year-old patient with oculomotor schwannoma who underwent subtotal resection resulting in tumor recurrence 4 months following resection. The recurrent tumor was then treated with fractionated Cyberknife SRT; however, details of the dosage and fractionation regimen were not reported. Traditionally, fractionated radiotherapy without stereotactic immobilization, targeting, and beam guidance requires a setup error of 4e5 mm. This set-up error decreases the conformality of the dosing and increases the dose delivered to surrounding structures. In the case of the oculomotor nerve, the adjacent structures of concern include the optic apparatus and the mesial temporal structures. This lack of conformality increases the risk of delayed radiation effects such as optic neuropathy, neurocognitive decline, and development of secondary malignancies.55 In contrast, the Cyberknife (Accuray, Inc.) is a stereotactic linear accelerator radiation source mounted to a robot arm, which tracks patient movement in near real time as the treatment is delivered. As such, the set-up error is reduced or
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eliminated. It has been shown to have a similar dose conformality to Gammaknife radiosurgery with similar tumor control rates in multiple pathologies.56 Cyberknife (Accuray, Inc.), however, has the benefit of not requiring a stereotactic frame to be placed because of the sophisticated ongoing image guidance. This can be of particular benefit in the pediatric population, as it spares the morbidity of head frame placement allowing protracted fractionation. With the highly conformal dose distribution and the fractionation scheme, Cyberknife (Accuray, Inc.) combines the benefits of SRS with traditional fractionation. In the pediatric population, the greatest concern for delivering radiation to a benign disease process are the delayed effects of radiation (e.g., neurocognitive effects and secondary malignancy). Fractionated Cyberknife (Accuray, Inc.) SRT has theoretical benefit over traditionally fractionated external beam radiotherapy by using marginless treatment to limit the exposure of surrounding structures to high-dose radiation. Therefore, Fractionated Cyberknife (Accuray, Inc.) SRT theoretically diminishes the risk of neurocognitive decline, optic neuropathy, and secondary malignancy that may be associated with high-dose radiation to oculomotor schwannomas. This is accomplished, however, by a trade-off of larger volumes of low-dose exposure, which, while not associated with focal neurologic deficits, may be associated with global neurocognitive problems and out-of-field secondary cancer. As such, long-term follow-up is required. Our 2 patients are the first described cases of oculomotor nerve schwannomas to be treated with traditionally fractionated Cyberknife (Accuray, Inc.) SRT. Both of our patients, who were treated with 45e50 Gy administered over 25 fractions, achieved long-term tumor control with no symptomatic progression, no treatment complications, and no cognitive deficits at nearly 5-year follow-up (1 patient demonstrated a radiologic decrease in tumor volume at 30 months). The clinical and radiologic results achieved with fractionated Cyberknife (Accuray, Inc.) SRT stand in stark contrast to the morbidity and possible tumor recurrence experienced in microsurgical patients.
Limitations All studies included in this systematic review were case series or case reports, which are limited by small sample size and selection bias. This is an inherent limitation of retrospective review of the literature. Due to the rarity of the disease, it would be difficult to test our treatment paradigm on a large cohort of patients. However, our case illustrations and reported outcome show that fractionated Cyberknife (Accuray, Inc.) SRT can be considered in select cases of oculomotor schwannomas. CONCLUSIONS The success of our reported treatment paradigm provides novel approach to be added to the armamentarium of treatment options for these incredibly rare and debilitating tumors in the pediatric population. Long-term follow-up is required to better quantify late effects of this approach. REFERENCES 1. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011e2015. Neuro Oncol. 2018;20(suppl_4):iv1-iv86. 2. Konovalov AN, Spallone A, Mukhamedjanov DJ, Tcherekajev VA, Makhmudov UB. Trigeminal neurinomas. A series of 111 surgical cases from a single institution. Acta Neurochir. 1996;138: 1027-1035. 3. Samii M, Migliori MM, Tatagiba M, Babu R. Surgical treatment of trigeminal schwannomas. J Neurosurg. 1995;82:711-718. 4. Sarma S, Sekhar LN, Schessel DA, Malis LI, Day JD. Nonvestibular schwannomas of the brain: a 7-year experience. Neurosurgery. 2002;50:437-449. 5. Tan LC, Bordi L, Symon L, Cheesman AD. Jugular foramen neuromas: a review of 14 cases. Surg Neurol. 1990;34:205-211. 6. Kida Y, Yoshimoto M, Hasegawa T. Radiosurgery for facial schwannoma. J Neurosurg. 2007;106: 24-29. 7. Symon L, Cheesman AD, Kawauchi M, Bordi L. Neuromas of the facial nerve: a report of 12 cases. Br J Neurosurg. 1993;7:13-22. 8. Plitt A, El Ahmadieh TY, Bindal S, Myers L, White J, Gluf W. Hypoglossal schwannoma of neck: case report and review of literature. World Neurosurg. 2018;110:240-243.
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41. Pollock BE, Foote RL, Stafford SL. Stereotactic radiosurgery: the preferred management for patients with nonvestibular schwannomas? Int J Radiat Oncol Biol Phys. 2002;52:1002-1007. 42. Huang C-F, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for trigeminal schwannomas. Neurosurgery. 1999;45: 11-15. 43. Martin JJ, Kondziolka D, Flickinger JC, Mathieu D, Niranjan A, Lunsford LD. Cranial nerve preservation and outcomes after stereotactic radiosurgery for jugular foramen schwannomas. Neurosurgery. 2007;61:76-81. 44. Hasegawa T, Kida Y, Yoshimoto M, Koike J. Trigeminal schwannomas: results of gamma knife surgery in 37 cases. J Neurosurg. 2007;106:18-23. 45. Zabel A, Debus J, Thilmann C, Schlegel W, Wannenmacher M. Management of benign cranial nonacoustic schwannomas by fractionated stereotactic radiotherapy. Int J Cancer. 2001;96: 356-362. 46. Pan L, Wang E-M, Zhang N, et al. Long-term results of Leksell gamma knife surgery for trigeminal schwannomas. J Neurosurg. 2005; 102(Special_Supplement):220. 47. Langlois A-M, Iorio-Morin C, Masson-Côté L, Mathieu D. Gamma knife stereotactic radiosurgery for nonvestibular cranial nerve schwannomas. World Neurosurg. 2018;110:e1031-e1039. 48. Persson O, Bartek J, Shalom NB, Wangerid T, Jakola AS, Förander P. Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review. Acta Neurochir. 2017;159:1013-1021.
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Received 16 March 2019; accepted 13 May 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.05.114 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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